Research Projects

The chronic or persistent pain that includes visceral, thermal, neuropathic pain, and pain associated with cancer is considered an unmet medical need. Morphinans are the most effective and widely used drugs for the treatment of severe pain. Despite the clinical usefulness of these compounds, the side effects such as respiratory depression, constipation, tolerance, physical dependence and addiction liabilities limits their uses. These morphinans exhibits their action through the activation of opioid receptors which are divided into four subtypes, μ (MOR), κ (KOR), δ (DOR) and nociceptin. When an agonist binds to the opioid receptor, it activates G proteins, inhibit adenylate cyclase, and promote the extrusion of potassium ions. These events can finally lead to the hyperpolarization of cell membranes. These events also block or minimize the transmission of painful stimuli and raise the pain threshold. Mu opioid receptor (MOR) agonists are the most widely used opioids for treating pain, but induces tolerance, addiction, respiratory depression, and constipation. It has been discovered that k-opioid receptor (KOR) agonists also have the same role in development of analgesics with no addiction. Hence, development of new KOR agonist might fill the gap. From literature, we found that the plant derived alkaloids from kratom (Mitragyna speciose) and akuamma tree (Picralima nitida) showed potent KOR agonist activity. The plant alkaloid morphine isolated from Papaver somniferum showed high affinity for opioid receptors with the activation MORs which exerts its analgesic effect, however the addiction is the major drawback of morphine which restricted it use in the patients other than cancer’s. Recently, kratom alkaloids have shown potent analgesic effects via activation of kappa opioid receptors (KOR). Mitragynine, 7-OH mitragynine and a rearranged spiro indole alkaloid mitragynine pseudoindoxyl isolated from M. speciose which have shown more potent analgesic effects than morphine. Alstonia scholaris contains chemically similar compounds to kratam and akuamma alkaloids and its traditional application of various parts in the management of rheumatic and ulcerative pains supported our hypothesis. Hence, we done some preliminary work with alkaloid enriched fraction which showed significant KOR agonist activity with IC50 25.1 µg/ml. The TLC analysis of fraction showed number of alkaloids are present (+ve Dragondorff test) which need to be isolate and identify. With these findings and observations, we are very positive in the study to isolate active compound(s) with analgesic activity targeting one or other opioid receptor. In present proposal, we are interested to isolate and characterize alkaloids from Alstonia scholaris leaves for analgesic activity via modulating opioid receptor activity. We will also develop efficient, environment benign extraction methods and chemical signature profiling for ecotype and chemotype studies using different analytical techniques.